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An Integrated Approach for Microprotein Identification and Sequence Analysis
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An Integrated Approach for Microprotein Identification and Sequence Analysis

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LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane

Shan Zhang1,2, Yabo Guo1, Gio Fidelito2

  • 1Department of Biochemistry, Department of Cardiology of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.

Iscience
|September 4, 2023
PubMed

Insights

The microprotein Mitoregulin (MTLN), encoded by LINC00116, localizes to the outer mitochondrial membrane. Loss of MTLN impacts fatty acid metabolism and protects against insulin resistance.

Area of Science:

  • Mitochondrial biology
  • Molecular genetics
  • Metabolic regulation

Background:

  • The microprotein Mitoregulin (MTLN), encoded by LINC00116, was initially reported to localize to the inner mitochondrial membrane and regulate energy metabolism.
  • Conflicting reports exist regarding MTLN's precise submitochondrial localization and molecular functions, necessitating clarification.

Purpose of the Study:

  • To definitively determine the submitochondrial localization of MTLN.
  • To elucidate the molecular function of MTLN in relation to fatty acid metabolism.
  • To investigate the physiological consequences of MTLN loss, particularly in the context of metabolic disease.

Main Methods:

  • Utilized orthogonal methods, including split GFP-based reporters, for accurate microprotein topology analysis.
  • Investigated protein-protein interactions of MTLN with enzymes involved in fatty acid metabolism.
  • Assessed the impact of MTLN loss on very long-chain fatty acid (VLCFA) levels and insulin sensitivity in mice.

Main Results:

  • Unequivocally demonstrated MTLN's primary localization to the outer mitochondrial membrane.
  • Identified interactions between MTLN and fatty acid metabolism enzymes CPT1B and CYB5B.
  • Observed accumulation of VLCFAs, including docosahexaenoic acid (DHA), upon MTLN loss.
  • Showed that MTLN deficiency confers protection against diet-induced insulin resistance in mice.

Conclusions:

  • MTLN is an outer mitochondrial membrane protein that regulates VLCFA metabolism.
  • MTLN deficiency protects against diet-induced insulin resistance, highlighting a role for VLCFAs in this protective effect.
  • MTLN represents a potential therapeutic target for modulating VLCFA catabolism and metabolic health.
Keywords:
BiochemistryBiological sciencesCell biologyMolecular biology

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